Oral leukoplakia is a mucosal disease with a high canceration rate--estimated to range between 0% and 20% over 20 years, see e.g. Metha F. S., Pindborg J. J., Gupta P. C., Daftrary D. K. Epidemiologic and histologic study of oral cancer and leukoplakia among 50,915 villages in India, Cancer 1969, 24, 832-849. Surgical removal is considered the best therapy, see e.g. Frame J. W., Dasgupta A. R., Dalton G. A. Use of the carbon dioxide laser in the management of premalignant lesions of the oral mucosa, J. Laryngol Otol 1984, 98, 1251-1260. Many patients operated on for oral leukoplakia later develop local relapses, new leukoplakias or squamous cell carcinomas. This finding is consistent with the field cancerization concept introduced by Slaughter in 1953 for head and neck cancers: a whole tissue region repeatedly exposed to carcinogenic insult (tobacco, alcohol) is at an increased risk for developing multiple independent foci of malignant lesions see e.g., Slaughter D. P., Soutwick H. W., Smejkal W. "Field cancerization" in oral stratified squamous epithelium: clinical implications of multicentric origin, Cancer 1953, 6, 963-968. These considerations were believed by the inventors to justify chemo-preventive trials and the accessibility to the oral cavity allows convenient histological, photographic and size evaluation to assess intervention efficacy.
Over the last 10 years several studies have indicated that vitamin A and its derivatives are effective in the treatment of oral leukoplakias, although the mechanisms of such action are not completely understood. See e.g., Koch H. F., Biochemical treatment of precancerous oral lesions: the effectiveness of various analogues of retinoic acid. J. Maxillofac Surg. 1978, 6, 59-63; Shah J. P., Strong E. W., Decosse J. J., Iri L., Sellers P. Effect of retinoids on oral leukoplakia, Am. J. Surg. 1983, 146, 466-470; Stich H. F., Hornby A. P., Dunn B. P. A pilot beta-carotene interventional trial within units using smokeless tobacco, Int. J. Cancer 1985, 36, 321-327; Hong W. K., Endicott J., Itri L. M. et al. 13-cis-retinoic acid in the treatment of oral leukoplakia; N. Engl. J. Med. 1986, 315, 1501-1505; and Garewal H. S., Meyskens F. L. Jr., Killen D., et al. Response of oral leukoplakia to beta-carotene. J. Clin. Oncol. 1990, 8, 1715-1720. These compounds have also been shown to be effective in modulating the growth of premalignant cells and suppressing their progression to neoplasia, see e.g., Meyskens F. L. Chemoprevention, In: Wittes R. E., ed. Cancer Investigation and Management. Chichester, John Wiley & Sons, 1985, 2, 275-283. In a recent randomized study it was shown that 13-cis-retinoic acid is efficacious in preventing the development of second primary tumors in patients disease-free after local therapy for squamous cell carcinoma of the head and neck, Hong W. K., Lippman S. M., Itri L. M., et al. Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck. N. Engl. F. Med. 1990, 323, 795-801.
Despite the effectiveness of such retinoid treatments, it has been universally found that therapeutic doses of these retinoids cause severe side effects (skin dryness, cheilitis, hypertriglicer-dermia and conjunctivitis) and many patients are unable to continue therapy, Sporn MB, Newton DL. Chemoprevention of cancer with retinoids, Fed. Proc. 1979, 38, 2528-2534. It is therefore an object of the present invention to provide a retinoid which is therapeutically effective for treating leukoplakia and inhibiting the development of malignant lesions but is safely tolerated by patients being treated thereby.